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| 1 | INT-767 improves histopathological features in a dietinduced ob/ob mouse model of biopsy-confirmed nonalcoholic steatohepatitis显示文摘AIM To characterize the efficacy of the dual FXR/TGR5 receptor agonist INT-767 upon histological endpoints in a rodent model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis(NASH).METHODS The effects of INT-767 on histological features of NASH were assessed in two studies using Lep^(ob/ob)(ob/ob) NASH mice fed the AMLN diet(high fat with transfat, cholesterol and fructose). In a proof-of-conceptstudy, Lep^(ob/ob)(ob/ob) NASH mice were first dosed with INT-767(3 or 10 mg/kg for 8 wk). A second ob/ob NASH study compared INT-767(3 and 10 mg/kg) to obeticholic acid(OCA)(10 or 30 mg/kg; 16 wk). Primary histological endpoints included qualitative and quantitative assessments of NASH. Other metabolic and plasma endpoints were also assessed. A comparative assessment of INT-767 and OCA effects on drug distribution and hepatic gene expression was performed in C57 Bl/6 mice on standard chow. C57 Bl/6 mice were orally dosed with INT-767 or OCA(1-30 mg/kg) for 2 wk, and expression levels of candidate genes were assessed by RNA sequencing and tissue drug levels were measured by liquid chromatography tandem-mass spectrometry.RESULTS INT-767 dose-dependently(3 and 10 mg/kg, PO, QD, 8 wk) improved qualitative morphometric scores on steatohepatitis severity, inflammatory infiltrates and fibrosis stage. Quantitative morphometric analyses revealed that INT-767 reduced parenchymal collagen area, collagen fiber density, inflammation(assessed by Galectin-3 immunohistochemistry) and hepatocyte lipid droplet area following INT-767 treatment. In a comparative study(16 wk), the FXR agonists OCA(10 and 30 mg/kg) and INT-767(3 and 10 mg/kg) both improved NASH histopathology, with INT-767 exerting greater therapeutic potency and efficacy than OCA. Mechanistic studies suggest that both drugs accumulate similarly within the liver and ileum, however, the effects of INT-767 may be driven by enhanced hepatic, but not ileal, FXR function. CONCLUSION These findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH. | Jonathan D Roth Michael Feigh Sanne S Veidal Louise KD Fensholdt Kristoffer T Rigbolt Henrik H Hansen Li C Chen Mathieu Petitjean Weslyn Friley Niels Vrang Jacob Jelsing Mark Young | 2018 | World Journal of Gastroenterology2018，24，2： | 7 |
| 2 | Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial显示文摘 | JY Douillard D Cunningham AD Roth M Navarro RD James P Karasek P Jandik T Iveson J Carmichael M Alakl G Gruia L Awad P Rougier | 2000 | The Lancet2000，，9209： | 4 |
| 3 | How to make ends meet显示文摘 | Roth D Lindld T Gellert M | 1995 | Current Biology1995，5，： | 1 |
| 4 | A New family of mesoporous molecular sieves prepared with liquid crystal templates显示文摘 | BECK J S VARTULI J C ROTH W J LEONOWICZ M E KRESGE C T SCHMITT K D CHU C T W OLSON D H SHEPPARD E W | 1992 | J Am Chem Soc1992，114，10： | 1 |
| 5 | Comprehensive mapping of the human kinome to epidermal growth factor receptor signaling显示文摘 | Komurov K Padron D Cheng T Roth M Rosenblatt K.P White M.A | | 0，，： | 1 |
| 6 | Effect of the estrogen Recept or locus on reproduction and production t rait s in f our Commercial Pig Lines 显示文摘 | SHORT T H ROTH SCHILDOI SOUTHWOOD D G | 1997 | Anim Sci1997，75，12： | 1 |
| 7 | Synthesis of'porphyrin-linker-thiol'molecules with diverse linkers for studies of molecular-based information storage显示文摘 | GRYKO D T CLAUSEN C ROTH K M | 2000 | The Journal of Organic Chemistry2000，65，22： | 1 |
| 8 | Roles of Subsidiary Managers in Multinational Corporations: The Effect of Dual Organizational Identification 显示文摘 | Vora D Kostova T Roth K | 2007 | Management International Review2007，47，4： | 1 |
| 9 | Manufacturing aspectsrelating to the effects of direct current on the tensile propertiesof metals 显示文摘 | Ross C D Irvin D B Roth J T | | Journal o f Engineering Materials andTechnology0，29，2： | 1 |
| 10 | Preoperative assess- ment of the emlcellous t ne mineral density of the pr:ximal humerus using CT data显示文摘 | Kcappinger D Roth T Gsehwentner M | 2012 | Skeletal Radiol2012，41，3： | 1 |
| 11 | An analysis of operating performance and firm characteristics around open market share repurchases 显示文摘 | NIXON T D ROTH G SAPORSCHENKO A | 2010 | Journal of Finance and Accountancy2010，6，3： | 1 |
| 12 | Altered photosynthesis,flowering and fruiting in transgenic tomato plants that have an increased capacity for sucrose synthesis显示文摘 | Micallef B J Haskin K A Vanderveer P J Roth K S Shewmaker C K Sharkey T D | | 0，，： | 1 |
| 13 | Microglia development and function显示文摘 | NAYAK D ROTH T L MCGAVERN D B | 2014 | Annu Rev Immunol2014，，32： | 1 |
| 14 | A new family of mesoporous molecular sieves prepared with liquid crystal templates 显示文摘 | BECK J S VARTULI J C ROTH W J LEONOWICZ M E KRESGE C T SCHNITT K D CHU C T-W OLSON D H SHEPPARD E W McCULLEN S B HIGGINS J B SCHLENKER J L | 1992 | J Am Chem Soc1992，114，10： | 1 |
| 15 | Effect of dc on the Formability of Ti-6A1-4V显示文摘 | Ross C D Kronenberger T J Roth J T | 2009 | Journal of Engi- neering Materials and Technology2009，131，3： | 1 |
| 16 | A review of the effects of pregabalin on sleep disturbance across multiple clinical conditions显示文摘 | Roth T Arnold LM Garcia-Borreguero D | 2013 | Sleep Med Rev2013，9，： | 1 |
| 17 | a new prediction equation,A more accurate method to estimate glomerular filtration rate from serum creatinine,Modification of diet in renal disease study group显示文摘 | Levy A S Bosch J P Lewis J B Greene T Rogers N Roth D Ann Intern Med | | 0，，： | 1 |
| 18 | Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia显示文摘 | Roth T Seiden D Sainati S | 2006 | Sleep Med2006，7，4： | 1 |
| 19 | Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists显示文摘 | Crockett E T Galligan J J Uhal B D Harkema J Roth R Pandya K | 2006 | BMC Clin Pathol2006，6，： | 1 |
| 20 | A 2-night, 3- period, crossover study of ramelteon' s efficacy and safe- ty in older adults with chronic insomnia显示文摘 | Roth T Seiden D Wang-Weigand S | 2007 | Curr Med Res Opin2007，23，5： | 1 |
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